p53-mediated Upregulation of MKP-3 Contributes to the Establishment of Cellular Senescent Phenotype through Dephosphorylation of ERK1/2 [Signal Transduction]

November 20th, 2014 by Zhang, H., Chi, Y., Gao, K., Zhang, X., Yao, J.

Growth arrest is one of the essential features of cellular senescence. At present, the precise mechanisms responsible for the establishment and maintenance of senescence-associated arrested phenotype are still incompletely understood. Given that ERK1/2 is one of the major kinases controlling cell growth and proliferation, we examined the possible implication of ERK1/2. Exposure of normal rat epithelial cells to etoposide caused cellular senescence, as manifested by the enlarged cell size, flattened cell body, reduced cell proliferation, enhanced β-galactosidase activity, elevated p53 and p21. Senescent cells displayed a blunted response to growth factor-induced cell proliferation, which was preceded by impaired ERK1/2 activation. Further analysis revealed that senescent cells expressed significantly higher level of mitogen-activated protein phosphatase-3 (MKP-3, a cytosolic ERK1/2-targeted phosphatase), which was suppressed by blocking transcriptional activity of the tumor suppressor p53 with pifithrin-α. Inhibition of MKP-3 activity with specific inhibitor or siRNA enhanced basal ERK1/2 phosphorylation and promoted cell proliferation. Apart from its role in growth arrest, impairment of ERK1/2 also contributed to the resistance of senescent cells to oxidant-elicited cell injury. These results thus indicate that p53-mediated upregulation of MKP-3 contributes to the establishment and maintenance of senescent cellular phenotype through dephosphorylating ERK1/2. Impairment of ERK1/2 activation could be an important mechanism by which p53 controls cellular senescence.
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